<p>Metabolic syndrome is characterized by insulin resistance, dyslipidemia, oxidative stress, and chronic inflammation, all of which contribute to diabetes and cardiovascular complications. This study investigated the therapeutic and toxicological effects of conventional Tenoxicam (TNX-Tab) and nano-formulated Tenoxicam (TNX-NF), encapsulated in HPβCD nanosponges, in a rat model of dexamethasone-induced metabolic syndrome. TNX-loaded nanosponges showed favorable physicochemical properties and sustained drug release. In the in vivo study, sixty male Sprague–Dawley rats were assigned to six groups and treated with dexamethasone, TNX-Tab, TNX-NF, or their combinations. Metabolic, inflammatory, oxidative, renal, and hepatic markers were evaluated, together with pancreatic histopathology and insulin immunofluorescence. Dexamethasone induced marked metabolic and pancreatic alterations, including hyperglycemia, insulin resistance, inflammation, oxidative stress, dyslipidemia, and tissue damage. Both TNX formulations attenuated several of these disturbances. TNX-NF showed better effects on IL-4 and HDL, whereas TNX-Tab demonstrated a more favorable effect on insulin resistance and IL-6 reduction. However, TNX-NF did not show consistent overall superiority and was associated with higher ALT, BUN, urea, and creatinine levels, suggesting possible hepatic and renal burden. Histopathological and immunofluorescence findings confirmed partial restoration of pancreatic architecture and insulin expression in both treatment groups, whereas immunohistochemical analysis showed no significant differences across all treatment groups. Overall, both formulations showed protective effects, but the nanoformulation offered selective advantages rather than clear overall superiority, indicating that further optimization is needed.</p> Graphical Abstract <p></p>